Gper proteolytic targeting chimeras

Abstract

A molecule comprising a G-protein coupled estrogen receptor (GPER) ligand coupled to a linker coupled to an E3 ubiquitin ligase ligand and methods of using the molecule are provided. In one embodiment, the GPER ligand is estradiol and the E3 ubiquitin ligase ligand is (S,R,S)- AHPC.

What is claimed is: 
     
         1 . A molecule comprising a G-protein coupled estrogen receptor (GPER) ligand coupled to a linker coupled to an E3 ubiquitin ligase ligand. 
     
     
         2 . The molecule of  claim 1  wherein the GPER ligand comprises 17β-estradiol, estrone, a phytoestrogen, a xenoestrogen, estriol, estriol 3-sulfate, estriol 17-sulfate, G-1, G-15, G-36, genistein, dazine, or quercetin. 
     
     
         3 . The molecule of  claim 2  wherein the phytoestrogen comprises a flavone, isoflavone, lignin saponin, coumestin, or stilbene. 
     
     
         4 . The molecule of  claim 1  wherein the GPER ligand is a GPER antagonist. 
     
     
         5 . The molecule of  claim 1  wherein the E3 ubiquitin ligase ligand is a Von Hippel ligase (VHL) ligand. 
     
     
         6 . The molecule of  claim 1  wherein the E3 ubiquitin ligase ligand comprises cereblon, lenalidomide, pomalidomide, iberdomide, (S,R,S)-AHPC, thalidomide, VH-298, CC-122, CC-885, E3ligase ligand 8, TD-106, VL285, VH032, VH101, VH298, VHL ligand 4, VHL ligand 7, VHL-2 ligand 3, E3 ligase ligand 3, E3 ligase ligand 2, or BC-1215. 
     
     
         7 . The molecule of  claim 1  wherein the linker has a chain having 10 to 50 atoms. 
     
     
         8 . The molecule of  claim 7  wherein the linker is an alkyl linker or a heteroalkyl linker or comprises polyethylene glycol (PEG). 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The molecule of  claim 8  wherein the linker comprises 3 to 15 PEG units or comprises (PEG) m NH(CO)(PEG) n  where n and m independently are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. 
     
     
         12 . (canceled) 
     
     
         13 . The molecule of  claim 11  wherein n is 3, 4, 5, or 6 or wherein m is 7, 8, 9, or 10. 
     
     
         14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising an amount of the molecule of  claim 1 . 
     
     
         16 - 19 . (canceled) 
     
     
         20 . A method to prevent, inhibit or treat a cancer in a mammal, comprising: administering to the mammal a composition having an effective amount of a molecule comprising a G-protein coupled estrogen receptor (GPER) ligand coupled to a linker coupled to an E3 ubiquitin ligase ligand. 
     
     
         21 . The method of  claim 20  wherein the cancer is a GPER positive cancer. 
     
     
         22 . The method of  claim 20  wherein the cancer is an endocrine resistant cancer or a hormonal therapy resistant cancer. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 20  wherein the cancer is a triple negative breast cancer. 
     
     
         25 . The method of  claim 20  wherein the cancer is a gynecological cancer. 
     
     
         26 . The method of  claim 20  wherein the cancer is ovarian cancer or endometrial cancer. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 20  wherein the mammal is a human. 
     
     
         29 . The method of  claim 20  8 wherein the administration is systemic. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 20  wherein the composition is a sustained release dosage form. 
     
     
         32 . (canceled)